Atropisomeric Amides as Chiral Ligands: Using (−)-Sparteine-Directed

J. Org. Chem. 2000, 65, 7033-7040

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Atropisomeric Amides as Chiral Ligands: Using (-)-Sparteine-Directed Enantioselective Silylation to Control the Conformation of a Stereogenic Axis Jonathan Clayden,* Paul Johnson, Jennifer H. Pink, and Madeleine Helliwell Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K. [email protected] Received May 8, 2000

An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermodynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation and functionalization of the amide in the 6-position allows the single amide conformer to be trapped as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute configuration, whose barriers to racemization have been determined by polarimetry. Enantiomerically pure amides bearing phosphine substituents are effective ligands in a Pd-catalyzed allylic substitution reactionsthe first use of a nonbiaryl atropisomer as a chiral ligandsand give products with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced by the presence of palladium. Introduction Atropisomeric biaryls are well established as one of the most important classes of ligands for asymmetric metalcatalyzed reactions.1 The angled aromatic rings serve as a useful scaffold for the attachment of metal-coordinating heteroatoms, and biaryl-complexed transition metals provide modern chemistry with some of its most powerful asymmetric catalysts.2

Nonbiaryl atropisomers, on the other hand, have never been used as chiral ligands.3 A number of types of nonbiaryl atropisomers are known,4 and most prominent among them recently have been the chiral tertiary amides 15 and the chiral anilides 2.6 Both types have a powerful ability to control relative stereochemistry in the racemic series,7,8 and both have been used as chiral * To whom correspondence should be addressed. Fax: 0161 275 4939. (1) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992, 503. (2) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (3) Clayden, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 949. (4) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994. (5) Clayden, J. Synlett 1998, 810. (6) Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955. (7) For reactions of atropisomeric anilides in the racemic series, see ref 6: Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131; Bach, T.; Schro¨der, J.; Harms, K. Tetrahedron Lett. 1999, 40, 9003.

auxiliaries.9,10 Single enantiomers of compounds related to 1 have been made by kinetic resolution using (-)sparteine,11 by atroposelective transformation of an enantiomerically pure arene-chromium tricarbonyl complex,12 and by a dynamic resolution under thermodynamic control using a proline-derived diamine as the source of asymmetry.13 Conformational stability sufficient for the existence of atropisomers requires severe steric hindrance, and this leads to the unreactivity that prevents the successful recycling of chiral auxiliaries derived from 1 and 2. Our aim more recently has therefore been to synthesize single enantiomers of amides 1 for use, not as auxiliaries, but as chiral ligands for metal-catalyzed asymmetric reactions. We set out to make bidentate target ligands containing a second point of coordination (in addition to the amide O or N) which we would introduce using the amides’ versatile ortholithiation chemistry.14 (8) For reactions of atropisomeric benzamides and naphthamides in the racemic series, see refs 15-17: Bowles, P.; Clayden, J.; Tomkinson, M. Tetrahedron Lett. 1995, 36, 9219. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1996, 37, 5577. Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38, 2561. Clayden, J.; Darbyshire, M.; Pink, J. H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1997, 38, 8587. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1999, 40, 3329. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1999, 40, 7883. (9) Atropisomeric anilides as chiral auxiliaries: Hughes, A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S. Tetrahedron Lett. 1996, 37, 7607. Hughes, A. D.; Simpkins, N. S. Synlett 1998, 967. Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295. Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997, 38, 4447. Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T. J. Org. Chem. 1998, 63, 2634. Kitagawa, O.; Momose, S.-i.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett. 1999, 40, 8827. (10) Atropisomeric naphthamides as chiral auxiliaries: Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron Lett. 2000, 41, 3279. (11) Thayumanavan, S.; Beak, P.; Curran, D. P. Tetrahedron Lett. 1996, 37, 2899. (12) Koide, H.; Uemura, M. J. Chem. Soc., Chem. Commun. 1998, 2483. (13) Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. Engl. 1999, 38, 2556.

10.1021/jo0007074 CCC: $19.00 © 2000 American Chemical Society Published on Web 09/19/2000

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The potential thermal lability of a chiral axis makes thermodynamically controlled equilibration an attractive method for the synthesis of single atropisomeric diastereoisomers. The proline-derived diamine mentioned above13 exerts its effect by favoring one diastereoisomeric conformer over the other at equilibrium. In general, a stereogenic center bearing sterically well differentiated groups S, M, and L becomes conformationally interlocked with an adjacent tertiary amide, resulting in a strong preference for a single axial conformation.5 For example, with R1 ) H, conformer 3a is significantly favored over conformer 3b when S ) H, M ) Me, L ) R3Si,15 or S ) H, M ) NHMe, L ) secondary alkyl.16 For such 2-substituted benzamides, the diastereoisomeric conformers about the Ar-CO bond interconvert rapidly (on the laboratory, though not the NMR, time scale), with a halflife of 97% ee, and this material was used for all subsequent reactions. From the X-ray crystal structure (Figure 1) of (S)-5, we were able to confirm its absolute stereochemistry, which in earlier work had been deduced by conversion to a compound of known optical rotation.21 Figure 1b shows the X-ray crystal structure of 5 viewed along the Ar-CH(Me)SiMe3 bond. It indicates that the conformation of 5 in the crystalline state is in accord with our proposal that compounds of the general structure 3 adopt a conformation 3a, though it does not prove that this conformation is preferred in solution. We were, however, able to use 1H NMR to deduce that (S)-5 exists in predominantly one conformer about its Ar-CO axis in CDCl3. The Ar-CO rotation of 2-substituted tertiary benzamides, while not leading to separable atropisomers, is typically slow on the NMR time scale.18 When the interconverting conformers are enantiomeric, this slow rotation manifests itself in the appearance of two pairs of diastereotopic doublets corresponding to the diastereotopic N-i-Pr2 methyl groups. For (-)-5, Ar-CO rotation leads to diastereoisomeric conformers, which we would expect to see as two complete sets of signals in

Atropisomeric Amides as Chiral Ligands

J. Org. Chem., Vol. 65, No. 21, 2000 7035

Figure 2. X-ray crystal structure of 8d.

Scheme 3. Enantioselective Synthesis of Atropisomeric Amidesa

Figure 1. X-ray crystal structure of (S)-5: (a) viewed from front; (b) viewed along Ar-CH(Me)SiMe3 bond. Table 1. Enantioselective Synthesis of Atropisomeric Amides electrophile

R

acetone MeI Ph2P(O)Cl Ph2PCl PhSSPh

Me2C(OH)MePh2P(O)Ph2PPhS-

8, yield 9, yield (%) (%) 8, [R]23D 9, [R]23D 8a, 50 8b, 98 8c, 81 8d, 79 8e, 87

9a, 99 9b, 99 9c, 99 9d, 86 9e, 100

+42.5 +18.9 +40.3 -44.0 -28.9

+32.0 +3.2 +18.0 -4.0 -29.2

the 1H NMR spectrum at ambient temperature. The 1H NMR spectrum of (-)-5 shows these two sets of signals in a ratio of 10:1, indicating that (-)-5 is 90% one conformer about the Ar-CO axis at ambient temperature. Trapping the major conformer of (-)-5 as a major atropisomer allowed us to cash in the absolute stereochemistry of the silicon-bearing center. To do this, rotation of the amide group was blocked with a second ortho substituent on the benzamide ring. The amide (-)-5 was treated with s-BuLi to ortholithiate it,14 and the organolithium was quenched with the range of electrophiles shown in Table 1 to give 8a-e (Scheme 3). The NMR spectra of the crude reactions mixtures indicated >10:1 atroposelectivity (in some cases much higher36) in these reactions, and all of the products were obtained as

single diastereoisomeric atropisomers (by 1H NMR) after purification by chromatography. Oxidation of 8d to 8c was minimized by using a nonaqueous workup procedure. The final step in the asymmetric synthesis required removal of the silyl group to leave single enantiomeric atropisomers. Protodesilylation was easily achieved for all five compounds 8a-e by treatment with TBAF at 20 °C for 5 min, giving 9a-e (Scheme 3 and Table 1). The stereochemistry of 8d was proved by X-ray crystal structure determination (Figure 2), which, although it could not re-confirm the absolute stereochemistry of the compound, did confirm the relative stereochemistry between the stereogenic center and the amide axis, which remains as shown for 5. Presumably, therefore, the major conformer of 5 in solution, whose lithiation leads to 8, has the same Ar-CO conformation as that shown by 5 in the crystalline state. Figure 2 also clearly indicates the perpendicular arrangement of the ring and the amide group, and the continued conformational preference of the (trimethylsilyl)ethyl substituent. The enantiomeric purity of 9b was confirmed to be >98% ee by 1H NMR in the presence of the chiral solvating agent (+)-TFAE,22 which clearly split the ArMe singlet of racemic 9b into two enantiomeric signals. Barriers to Racemization of the Atropisomers. Although compounds 9 are still 2,6-disubstituted benzamides, and are therefore expected to be kinetically stable to racemization,18 their silylated precursors 8 had, additionally, thermodynamic stability relative to their atropisomeric diastereoisomers (see discussion below and Scheme 5). With this thermodynamic resistance to ArCO rotation removed, there was a danger that slow racemization of 9 might take place even at room temperature. We assessed the ease of racemization of each of the final products by following the first-order decay in optical rotation with time at a suitable temperature. The Eyring equation23 was used to derive a value for ∆Gqrac from the rate constant k. For 9d we repeated the

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Clayden et al.

Table 2. Rate of Racemization of Atropisomeric Amides entry 1 2 3 4 5 6 7 8 9 10 11 a

amide 9a 9b 9c 9d 9d 9d 9e 9b 9d 9d 9d

R Me2C(OH)Me Ph2P(O)Ph2P Ph2P Ph2P PhS Me Ph2P Ph2P Ph2P

additivea

[PdCl(π-allyl)]2 [PdCl(π-allyl)]2 Ti(OEt)2 AlMe3

T/°Cb

k/10-5 s-1

∆Gqrac/kJ mol-1

t1/225rac

93c

1.04 ( 0.03 2.76 ( 0.01 7.65 ( 0.07 18.7 ( 0.1 5.17 ( 0.005 1.49 ( 0.01 21.40 ( 0.07 2.27 ( 0.15 2400 ( 50 5.30 ( 0.04 4.83 ( 0.14

125.2 ( 0.3 107.5 ( 0.3 104.8 ( 0.3 104.0 ( 0.3 104.2 ( 0.3 104.0 ( 0.3 98.8 ( 0.3 108.1 ( 0.5 87.9 ( 0.3 104.1 ( 0.3 104.4 ( 0.5

30 years 10 days 3 days 2 days 2 days 2 days 6 hours 10 days 5 min 2 days 2 days

50 50 55 45 35 40 50 45 45 45

1 equiv in metal. b (0.5 °C. c Dioxane as solvent.

experiment at three temperatures and determined that |∆Sqrac| < 30 J mol-1 K-1.24 On the basis of this assumption, we estimated half-lives for racemization of 9a-e at 25 °C. All of these values are presented in Table 2 (entries 1-7). Racemization was slowest with R ) alkyl, and 9a (with a tertiary alkyl substituent) had almost complete conformational stability (entry 1). Even 9b, with R ) Me (entry 2), racemised more slowly than the phosphorus compounds 9c and 9d (entries 3 and 4). We have already noted that a trialkylsilyl group provides a poor block to bond rotation,18 and this feature appears to be general for the second row elements, with sulfide 9e racemizing still more rapidly (entry 7). Phosphine 9d was nonetheless conformationally stable enough for us to hope for its successful application as a chiral ligand at room temperature or below and on time-scales shorter than 24 h. There was little difference between the rate of racemization of the phosphine 9d and the phosphine oxide 9c. The First Use of Nonbiaryl Atropisomers as Chiral Ligands. A wide range of heterosubstituted arylphosphines have been used as ligands in palladiumcatalyzed asymmetric allylic substitution reactions.25 Among the most successful of these are Trost’s amidophosphines, and many others are P,N or P,O-bidentate ligands. The stereoelectronics of such “soft-hard” ligandmetal complexes has been proposed as a key factor in the stereocontrol exerted by some of these ligands.26,27 Our first trial allylic substitutions were carried out with 8d, whose silyl group eliminates the danger of slow atropisomerization during the reaction by making it thermodynamically stable to epimerization. 1,3-Diphenylpropenyl acetate 10 and dimethyl malonate 11 were treated with 1 mol % Pd (as [PdCl(π-allyl)]2) in the presence of 0.5 mol % 8d as a chiral ligand (Scheme 4). The reaction took 3 days at 25 °C to give 60% yield of product (-)-12, which was formed with 90% ee (by chiral GC). We presume the asymmetric induction in this reaction arises from the chirality of the stereogenic axis of 8d, and that the silicon-bearing stereogenic center has little direct influence on the reaction center. We therefore expected a similar result with the silyl-“deprotected” (23) Eyring, H. Chem. Rev. 1935, 17, 65. (24) Activation entropies for bond rotations are frequently (Stewart, W. H.; Siddall, T. H. Chem. Rev. 1970, 70, 517) though not always (Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64, 9430) close to zero, and the assumption that ∆Sq ) 0 and that ∆Gq is invariant with temperature allows convenient estimates of racemization half-lives to be made. (25) Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395. (26) Frost, C. G.; Williams, J. M. J. Tetrahedron Lett. 1993, 34, 2015. (27) Reiser, O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547.

Scheme 4.

Asymmetric Allylic Substitution Using 8d as a Chiral Ligand

ligand 9d. However, when the reaction of 10 and 11 was repeated using this ligand, although the rate was similar (36% yield after 48 h) the product 12 was racemic. Moreover, the ligand 9d recovered from the reaction turned out to be optically inactive, rather than having the ca. 35-40% ee we would expect after 3 days at 25 °C (see Table 2, entry 4). To find out why 9d had racemized so quickly, its rate of racemization was re-determined in the presence of palladium (Table 2, entry 9). Remarkably, palladium caused the barrier to racemization to drop by 16 kJ mol-1, and the rate of racemization to increase 500-fold, giving an estimated half-life for the racemization of 9d at 25 °C in the presence of palladium of only 5 min. The lack of enantiomeric enrichment in the allylic substitution product is simply explained by the fact that racemization of the ligand occurs much faster than the substitution reaction. The increase in rate of racemization appears to be due both to the phosphine substituent and to the presence of palladium, since adding palladium to the methylsubstituted 9b (entry 8) had almost no effect on the rate of racemization. The hard, oxophilic Lewis acids Ti(OEt)4 and AlMe3 similarly had essentially no effect on the rate of racemization of the phosphine 9d (entries 10, 11). Discussion The novel strategy employed in the asymmetric synthesis of 9 is outlined in Scheme 5. The starting amide 4 is a pair of rapidly interconverting (small ∆Gqrac) enantiomeric (aR and aS) conformers about the Ar-CO bond. Asymmetric construction of the stereogenic center in 5 perturbs the populations of the conformers, favoring aR over aS. This thermodynamic perturbation of populations is then fixed kinetically, by introduction of the substituent R into 8. Now the thermodynamic perturbationsthe

Atropisomeric Amides as Chiral Ligands Scheme 5.

J. Org. Chem., Vol. 65, No. 21, 2000 7037 Strategy in the Asymmetric Synthesis of 9

stereogenic centerscan be removed, and the kinetic barrier to reestablishment of equilibrium (large ∆Gqrac) allows enantiomeric excess to be retained in the products 9. The Pd-catalyzed substitution reactions presumably involve phosphines 8d and 9d as bidentate ligands for Pd. Trost’s secondary amido-phosphine ligands28 are superficially similar in structure, and they too perform better when some degree of conformational restriction is introduced into the amide and C-P bonds, allowing chirality to be transferred from the ligand backbone to the metal. Our ligand has a soft (P) and a hard (probably N, but possibly O) coordination site, each surrounded by considerable steric encumbrance, and with few bonds able to rotate freely. Further investigation will be required before we can propose a detailed transition state for the reaction. As for the accelerated racemization of 9d in the presence of palladium - presumably, a P-Pd-N (or maybe a P-Pd-O) chelate stabilizes the transition state for Ar-CO rotation. Metal complexation is known to affect rates of C-N rotation in amides, with hard, oxophilic Lewis acids lowering the rate,29 and soft, azaphilic metals raising it.30 We have found, in a similar amide, that C-N rotation and Ar-CO rotation are interlocked, with the two occurring simultaneously through a gearing effect.31 In other cases, rates of C-N and Ar-CO rotation are closely matched, again pointing to interlocked rotation.18 Yet if the increased rate of Ar(28) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99. (29) Fussenegger, R.; Rode, B. M. Chem Phys Lett 1976, 44, 95. (30) Cox, C.; Ferraris, D.; Murthy, N. M.; Lectka, T. J. Am. Chem. Soc. 1996, 118, 5332. (31) Clayden, J.; Pink, J. H. Angew. Chem., Int. Ed. Engl. 1998, 37, 1937.

CO rotation in this case had been a consequence simply of an increased rate of C-N rotation due to N-Pd coordination, a similar effect would be expected for methyl-substituted 9b. Addition of the same palladium complex to 9b to resulted in no increase in rotation rate. Similarly, Ti and Al Lewis acids, which would be expected to slow C-N rotation, had no significant effect on ArCO rotation in 9d. While the racemization of 9d precludes the use of this, and similar, atropisomeric compounds as ligands for palladium, the use of conformational interlocking (such as that in 8d) to control the conformation around a ligand’s binding site is an important and more generally exploitable concept. The 90% ee obtained in the reaction of 8d is remarkble because presumably the palladium also lowers the barrier to atropisomerization of 8d. However, the silyl group makes 8d thermodynamically stable relative to its diastereoisomer and prevents it epimerising. We now aim to use the versatile lithiation chemistry of tertiary amides to develop a novel range of conformationally constrained ligands for use in this, and other, metal catalyzed reactions.

Experimental Section General Methods. Pentane was distilled under nitrogen from calcium hydride. tert-Butyl methyl ether, diethyl ether (referred to as “ether”) and tetrahydrofuran (THF) were distilled under nitrogen from sodium benzophenone ketyl. Dry solvents were transferred to reaction vessels by syringe. “Petrol” refers to redistilled bp 40-60 °C petroleum ether. (-)Sparteine was distilled at reduced pressure from calcium hydride directly before use. Commercial sec-butyllithium (as a solution in hexanes) was titrated using diphenylacetone tosylhydrazone prior to use. Melting points are uncorrected. Column chromatography was performed using the method of Still, Kahn and Mitra32 with Merck silica gel 60H (230-300

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mesh) as the stationary phase. Thin-layer chromatography was performed using Merck silica 60 F254 aluminum-backed plates. N,N-Diisopropyl-2-ethylbenzamide 4.21 sec-Butyllithium (9.48 mL, 1.3 M solution in cyclohexane, 12.32 mmol) was added dropwise to a solution of N,N-diisopropylbenzamide (2.30 g, 11.20 mmol) in THF (120 mL), cooled to -78 °C under an atmosphere of nitrogen. After 1 h at - 78 °C, ethyl iodide (1.79 mL, 22.40 mmol) was added. The solution was allowed to warm to room temperature, water (50 mL) was added, and the THF was removed under reduced pressure. The aqueous phase was extracted with dichloromethane (3 × 30 mL), and the combined extracts were washed with water (30 mL), dried over magnesium sulfate, and filtered. The solvent was evaporated, and the crude product was purified by column chromatography (eluting with 5% ethyl acetate in light petroleum) to give the amide 4 as a white crystalline solid (2.61 g, 100%): mp 90-92 °C (lit.21 mp 91-93 °C); Rf(petrol/EtOAc 9:1) 0.47; 1 H NMR (CDCl3, 300 MHz) δ 7.34-7.17 (3H, m), 7.11 (1H, d, J ) 7.3 Hz), 3.71 (1H, sept, J ) 7 Hz), 3.54 (1H, sept, J ) 7 Hz), 2.79-2.58 (2H, m), 1.61 (6H, d, J ) 7 Hz), 1.29 (3H, t, J ) 7.5 Hz), 1.14 (3H, d, J ) 7 Hz), 1.11 (3H, d, J ) 7 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.5, 139.8, 138.0, 128.5, 128.1, 125.6, 124.6, 50.6, 45.6, 25.6, 20.6, 20.6, 20.5, 20.4, 15.1. (S)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)benzamide 5.21 Freshly distilled (-)-sparteine (644 mg, 3 mmol, 1.2 equiv) was added to 2-ethylbenzamide 4 (582 mg, 2.5 mmol, 1 equiv) in a predried, nitrogen filled flask. Pentane (75 mL) and tert-butyl methyl ether (75 mL) were added, and the resulting solution degassed using three freeze-pump-thaw cycles. The solution was cooled to -78 °C, and sec-butyllithium (2 mL of a 1.4 M solution, 1.1 equiv) was added, turning the solution deep purple. After a further 1.5 h at -78 °C, trimethylsilyl chloride (0.5 mL, 1.5 equiv) was added. Stirring at -78 °C was continued for a further 7 h, after which the solution was pale red in color. Methanol (1 mL) was added, and the solution was allowed to warm to room temperature. Phosphoric acid (0.5 M aq) was added, and the mixture was extracted into ether. The organic layer was separated and washed again with phosphoric acid (0.5 M aq) and then with water, before being dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product as a viscous clear oil. The crude product was purified by column chromatography (eluting with petrol/EtOAc 19:1), to give the title compound 5 (708 mg, 93%), as a colorless, crystalline solid with an enantiomeric excess of 69% (by GC on chiral stationary phase). Successive recrystallization of this compound from petrol afforded material of 98% ee [by chiral GC: 25m × 0.32 mm 0.25u CP-Chirasil-DEX CB, retention times 77:08.1 (99.133%), 77:43.3 (0.867%)]. mp 71-72 °C (Lit.21 68-70 °C), Rf(petrol/EtOAc 19:1) 0.15; IR (film/CHCl3) 2962, 1632 cm-1; 1H NMR (CDCl , 300 MHz) δ 7.05-7.29 (5H, m), 3.67 (1H, 3 sept, J ) 6.5 Hz), 3.49 (1H, sept, J ) 6.5 Hz), 2.17 (1H, q, J ) 7.5 Hz), 1.57 (6H, t, J ) 6.5 Hz), 1.34 (3H, d, J ) 7.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), 1.04 (3H, d, J ) 6.5 Hz), 0.00 (9H, s) about 10% of less stable conformer visible at 3.81 (sept, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.6, 142.5, 137.4, 127.9, 126.4, 125.0, 124.4, 50.3, 45.5, 25.4, 20.6, 20.3, 16.3, -2.9; MS (CI) m/z (rel intensity) 306 (MH+, 100); HRMS (EI) calcd for C18H31NOSi (M+) 305.2175, found 305.2172 (0.9 ppm). Ortholithiation of Silylated Benzamide 5. sec-Butyllithium (1.1 equiv) was added to a solution of benzamide 5 (1 equiv) in THF (0.03M) at -78 °C. The resulting orange solution was then stirred at this temperature for 30 min, followed by addition of the electrophile (1.5 equiv). The reaction was allowed to warm to room temperature, poured into water, and extracted into EtOAc. The combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 8a-e. (S,Ra)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-6-(1hydroxy-1-methyl)ethylbenzamide 8a. By this method, benzamide 5 (153 mg) and acetone gave an oil which was (32) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

Clayden et al. purified by column chromatography (eluting with petrol/EtOAc 9:1) to yield the title compound 8a (91 mg, 50%) as a white solid: mp 83-84 °C; Rf(petrol/EtOAc 4:1) 0.37; IR (film/CHCl3) 3540 (br), 2958, 1602 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.21 (1H, t, J ) 8 Hz), 6.99 (2H, dq, J ) 1.5, 8 Hz), 3.66 (1H, sept, J ) 6.5 Hz), 3.51 (1H, sept, J ) 7 Hz), 3.11 (1H, br s), 2.34 (1H, q, J ) 7.5 Hz), 1.58 (6H, s), 1.57 (3H, d, J ) 7 Hz), 1.55 (3H, d, J ) 7 Hz), 1.37 (3H, d, J ) 7.5 Hz), 1.14 (3H, d, J ) 6.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), -0.05 (9 H, s); 13C NMR (CDCl3, 75 MHz) δ 173.1, 145.8, 143.2, 132.0, 127.2, 124.0, 123.2, 74.4, 50.5, 45.8, 34.9, 31.2, 24.2, 20.6, 20.3, 19.6, 19.5, 16.5, -2.8; MS (EI) m/z (rel intensity) 363 (M+, 30), 304 (53), 263 (100); HRMS (EI) calcd for C21H37NO2Si (M+) 363.2593, found 363.2587 (1.7 ppm); [R]23D +42.5 (CHCl3, c ) 1). (S,Ra)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-6methylbenzamide 8b. In the same way, benzamide 5 (153 mg) and methyl iodide gave an oil that was purified by column chromatography (eluting with petrol/EtOAc 19:1) to yield the title compound 8b (156 mg, 98%) as a white solid: mp 84-85 °C; Rf(petrol/EtOAc 19:1) 0.17; IR (film/CHCl3) 2960, 1628, cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.16 (1H, t, J ) 7.5 Hz), 6.96 (1H, d, J ) 7.5 Hz), 6.94 (1H, d, J ) 7.5 Hz), 3.69 (1H, sept, J ) 6.5 Hz), 3.52 (1H, sept, J ) 6.5 Hz), 2.30 (3H, s), 2.15 (1H, q, J ) 7.5 Hz), 1.62 (3H, d, J ) 6.5 Hz), 1.61 (3H, d, J ) 6.5 Hz), 1.35 (3H, d, J ) 7.5 Hz), 1.14 (3H, d, J ) 6.5 Hz), 1.10 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 170.0, 142.4, 136.6, 133.4, 127.3, 126.1, 123.4, 50.1, 45.6, 25.3, 21.0, 20.9, 20.3 (×2), 19.3, 16.4, -2.9; MS (CI) m/z (rel intensity) 320 (MH+, 100); HRMS (CI) calcd for C19H33NOSi (MH+) 319.2331, found 319.2325 (2.0 ppm); [R]23D +18.9 (CHCl3, c ) 3). Anal. Calcd for C19H33NOSi: C, 71.41; H, 10.41; N, 4.38. Found: C, 71.73; H, 10.04; N, 4.42. (S,Sa)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-6-diphenylphosphonylbenzamide 8c. In the same way, benzamide 5 (153 mg) and diphenylphosphinic chloride gave an oil which was purified by column chromatography (eluting with petrol/EtOAc 1:1) to yield the title compound 8 (204 mg, 81%) as a white solid: mp 165-167 °C, Rf(petrol/EtOAc 1:1) 0.23; IR (film/CHCl3) 2956, 2928, 1631, 1204 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.29-7.61, (11H, m), 7.18 (1H, dt, J ) 3, 7.5 Hz), 6.84 (1H, ddd, J ) 1, 7.5, 13.5 Hz), 3.66 (1H, sept, J ) 7 Hz), 3.51 (1H, sept, J ) 6.5 Hz), 2.44 (1H, q, J ) 7.5 Hz), 1.59 (3H, d, J ) 7 Hz), 1.49 (3H, d, J ) 7 Hz), 1.40 (3H, d, J ) 6.5 Hz), 1.39 (3H, d, J ) 7.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), -0.07 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 167.6 (d, J ) 3.5 Hz), 144.8 (d, J ) 10.0 Hz), 140.5 (d, J ) 8.0 Hz), 134.4 (d, J ) 103.0 Hz), 133.4 (d, J ) 105.5 Hz), 132.3 (d, J ) 9.0 Hz), 131.8 (d, J ) 10.5 Hz), 131.4 (d, J ) 3.5 Hz), 131.4 (d, J ) 3.0 Hz), 129.6 (d, J ) 13.0 Hz), 129.5 (d, J ) 3.0 Hz), 128.4 (d, J ) 100.5 Hz), 128.2 (d, J ) 12.0 Hz), 128.0 (d, J ) 5.5 Hz), 126.6 (d, J ) 13.5 Hz), 50.4, 45.8, 24.5, 21.2, 20.4, 19.7, 19.5, 16.1, -2.9; MS (CI) m/z (rel intensity) 506 (MH+, 100); HRMS (EI) calcd for C30H40NO2PSi (M+) 505.2566, found 505.2754 (1.6 ppm); [R]23D +40.3 (CHCl3, c ) 4). Anal. Calcd for C30H40NO2PSi: C, 71.25; H, 7.97; N, 2.77; P, 6.12. Found: C, 71.33; H, 8.09; N, 2.77; P, 6.27. (S,Sa)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-6-diphenylphosphinylbenzamide 8d. In the same way, benzamide 5 (153 mg) was lithiated and treated with chlorodiphenylphosphine. In place of the usual aqueous workup, the reaction was allowed to warm to room temperature and was then poured quickly through a pad of Celite. The flask and the Celite were washed with ether, and the filtrate was concentrated under reduced pressure. The resulting sticky oil was purified by column chromatography (eluting with petrol) to give the title compound 8d (193 mg, 79%) as a white foam, which crystallized from petrol as colorless needles: mp 140142 °C; Rf(petrol/EtOAc 9:1) 0.54; IR (film/CHCl3) 3053, 2956, 2871, 1629 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.19-7.36 (12H, m), 6.83-6.87 (1H, m), 3.84 (1H, sept, J ) 6.5 Hz), 3.57 (1H, sept, J ) 7 Hz), 2.32, (1H, q, J ) 7.5 Hz), 1.67 (3H, d, J ) 7 Hz), 1.59 (3H, d, J ) 7 Hz), 1.42 (3H, d, J ) 7.5 Hz), 1.31 (3H, d, J ) 6.5 Hz), 1.19 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 169.0 (d, J ) 5.0 Hz), 143.0 (d, J ) 35.5 Hz), 143.0 (d, J ) 8.0 Hz), 138.4 (d, J ) 12.0 Hz), 137.0 (d, J

Atropisomeric Amides as Chiral Ligands ) 11.0 Hz), 133.8 (d, J ) 15.5 Hz), 133.3 (d, J ) 19.0 Hz), 133.2 (d, J ) 19.5 Hz), 130.6 (d, J ) 2.0 Hz), 128.3 (d, J ) 6.0 Hz), 128.1 (d, J ) 4.0 Hz), 128.0 (d, J ) 6.5 Hz), 127.7, 126.8, 50.3, 45.8, 25.3, 21.1, 20.8 (d, J ) 6.0 Hz), 20.4, 20.0 (d, J ) 2.0 Hz), 16.1, -2.8; MS (CI) m/z (rel intensity) 490 (MH+, 100), 306 (35) 187 (70); HRMS (EI) calcd for C30H40NOPSi (M+) 489.2617, found 489.2622 (1.1 ppm); [R]23D -44.0 (CHCl3, c ) 2.68). Anal. Calcd for C30H40NOPSi: C, 73.58; H, 8.23; N, 2.86; P, 6.32. Found: C, 73.46; H, 8.29; N, 2.70; P, 6.32. (S,S a )-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-6phenylsulfanylbenzamide 8e. In the same way, benzamide 5 (76 mg) and diphenyl disulfide (55 mg, 1.5 equiv, as a solution in 2 mL of THF) gave a waxy crude product that was purified by column chromatography (eluting with petrol/EtOAc 19:1) to give the title compound 8e (90 mg, 87%) as a white solid: mp 140-142 °C; Rf(petrol/EtOAc 19:1) 0.27; IR (film/ CHCl3) 2960, 1631, cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.107.36 (6H, m), 7.00 (1H, dd, J ) 1, 8 Hz), 6.95 (1H, dd, J ) 1, 8 Hz), 3.72 (1H, sept, J ) 6.5 Hz), 3.51 (1H, sept, J ) 6.5 Hz), 2.21 (1H, q, J ) 7.5 Hz), 1.60 (3H, d, J ) 6.5 Hz), 1.57 (3H, d, J ) 6.5 Hz), 1.35 (3H, d, J ) 7.5 Hz), 1.19 (3H, d, J ) 6.5 Hz), 1.13 (3H, d, J ) 6.5 Hz), 0.00 (9H, s); 1H NMR (CDCl3, 75 MHz) δ 168.0, 143.9, 138.4, 136.1, 132.3, 131.0, 128.9, 128.2, 128.1, 126.8, 124.9, 50.4, 45.8, 25.6, 21.0, 20.8, 20.3, 20.1, 16.3, -2.8; MS (CI) m/z 414 (MH+, 100); HRMS (EI) calcd for C24H35NOSSi (M+) 413.2209, found 413.2223 (3.5 ppm); [R]23D -28.4 (CHCl3, c ) 1). Anal. Calcd for C24H35NOSSi: C, 69.68; H, 8.53; N, 3.39; S, 7.75. Found: C, 69.65; H, 8.84; N, 3.43; S, 7.92. Desilylation of Benzamides 8. TBAF (1 M solution in THF, 10 equiv) was added to a solution of the silylated amide 8 in THF (0.02M) at room temperature. The resulting solution was stirred for 5 min, then poured into cold water and extracted into ether. The combined extracts were dried (MgSO4) and concentrated under reduced pressure at 98%. Addition of (()-9b to the sample of (+)-9b proved the identity of this minor peak. (Sa)-N,N-Diisopropyl-2-ethyl-6-diphenylphosphonylbenzamide 9c. Silylated benzamide 8c (170 mg) was treated with TBAF according to the general procedure. Purification of the crude product by column chromatography (eluting with petrol/EtOAc 3:1 at ca. 0-5 °C) gave the title compound 9c (144 mg, 99%), as a white foam: Rf(petrol/EtOAc) 0.40; IR (film/CHCl3) 2975, 2929, 1630 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.59-7.67 (4H, m), 7.38-7.55 (7H, m), 7.23 (1H, dt, J ) 3.0, 8.0 Hz), 7.00 (1H, ddd, J ) 1.0, 7.5, 13.5 Hz), 3.68 (1H, sept, J ) 7.0 Hz), 3.50 (1H, sept, J ) 7.0 Hz), 2.80 (1H, dq, J ) 15, 7.5 Hz), 2.65 (1H, dq, J ) 15, 7.5 Hz), 1.55, (3H, d, J ) 7.0 Hz), 1.51 (3H, d, J ) 7.0 Hz), 1.36 (3H, d, J ) 6.5 Hz), 1.25 (3H, t, J ) 7.5 Hz), 1.10 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 167.6 (d, J ) 3.5 Hz), 142.1 (d, J ) 8.0 Hz), 141.4 (d, J ) 10.0 Hz), 134.1 (d, J ) 103.0 Hz), 132.9 (d, J ) 108.0 Hz), 132.2 (d, J ) 9.0 Hz), 131.9 (d, J ) 9.0 Hz), 131.8 (d, J ) 5.5 Hz), 131.5 (d, J ) 3.0 Hz), 131.5 (d, J ) 2.0 Hz), 131.0 (d, J ) 13.0 Hz), 128.3 (d, J ) 12.0 Hz), 128.1 (d, J ) 101.5 Hz), 128.1 (d, J ) 13.0 Hz), 126.9 (d, J ) 13.5 Hz), 51.0, 45.9, 25.1, 20.9, 20.3, 19.9, 19.7, 14.9; MS (EI) m/z (rel intensity) 434 (MH+, 100), 333 (20) 100 (42); HRMS (EI) calcd for C27H32NO2P (M+) 433.2171, found 433.2175 (1.0 ppm); [R]D23 +18.0 (CHCl3, c ) 1.6). Anal. Calcd for C27H32NO2P: C, 74.80; H, 7.44; N, 3.23; P, 7.14. Found: C, 74.56; H, 7.61; N, 3.05; P, 6.83. (Sa)-N,N-Diisopropyl-2-ethyl-6-diphenylphosphinylbenzamide 9d. Silylated benzamide 8d (112 mg) was treated with TBAF according to the general procedure. Purification of the crude product by column chromatography (eluting with petrol/EtOAc 9:1 at ca. 0-5 °C) gave the title compound 9d (82 mg, 86%) as white solid: mp 129-130 °C; Rf(petrol/EtOAc 4:1) 0.46; IR (film/CHCl3) 2969, 1628 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.22-7.38 (12H, m), 7.05 (1 H, ddd, J ) 1, 3.5, 7.5 Hz), 3.80 (1H, sept, J ) 6.5 Hz), 3.59 (1H, sept, J ) 6.5 Hz), 2.81 (1H, dq, J ) 15, 7.5 Hz), 2.67 (1H, dq, J ) 15, 7.5 Hz), 1.70 (3H, d, J ) 6.5 Hz), 1.63 (3H, d, J ) 6.5 Hz), 1.32 (3H, d, J ) 7.5 Hz), 1.24 (3H, d, J ) 6.5 Hz), 1.18 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 168.9 (d, J ) 5.0 Hz), 144.5 (d, J ) 36.5 Hz), 139.6 (d, J ) 8.5 Hz), 138.1 (d, J ) 11.5 Hz), 137.0 (d, J ) 11.5 Hz), 133.6 (d, J ) 15.5 Hz), 133.4 (d, J ) 19.5 Hz), 133.1 (d, J ) 19.0 Hz), 132.1 (d, J ) 2.5 Hz), 129.0, 128.3, 128.3 (d, J ) 5.5 Hz), 128.2 (d, J ) 7.5 Hz), 128.0, 127.8, 21.0, 20.8 (d, J ) 6.0 Hz), 20.5, 20.1 (d, J ) 2.0 Hz), 14.7; MS (EI) m/z (rel intensity) 418 (MH+, 10 - self-CI), 417 (M+, 8), 374 (50), 332 (100); HRMS (EI) calcd for C27H32NOP (M+) 417.2221, found 417.2218 (0.7 ppm); [R]D23 -4.0 (CHCl3, c ) 1). Anal. Calcd for C27H32NOP: C, 77.67; H, 7.72; N, 3.35; P, 7.42. Found: C, 77.38; H, 8.05; N, 3.31; P, 7.35. (Sa)-N,N-Diisopropyl-2-ethyl-6-phenylsulfanylbenzamide 9e. Silylated benzamide 8e (47 mg) was treated with TBAF according to the general procedure. Purification of the crude product by column chromatography (eluting with petrol/ EtOAc 9:1 at ca. 0-5 °C) gave the title compound 9e (42 mg, quantitative) as a white solid: mp 94-95 °C; Rf(petrol/EtOAc 4:1) 0.45; IR (film/CHCl3) 2971, 1630 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.51-7.54 (2H, m), 7.37-7.46 (3H, m), 7.27-7.29 (2H, m), 7.14-7.17 (1H, m), 3.83 (1H, sept, J ) 6.5 Hz), 3.67 (1H, sept, J ) 7 Hz), 2.87 (1H, dq, J ) 15, 7.5 Hz), 2.71 (1H, dq, J ) 15, 7.5 Hz), 1.75 (6H, t, J ) 7 Hz), 1.41 (3H, t, J ) 7.5 Hz), 1.36 (3H, d, J ) 6.5 Hz), 1.25 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 168.0 (DEPT: quat), 140.6 (quat), 139.3 (quat), 135.5 (quat), 132.3 (quat), 131.5 (CH), 129.2 (CH), 129.0 (CH), 128.3 (CH), 127.0 (CH), 126.7 (CH), 50.9 (CH), 45.9 (CH), 25.6 (CH2), 21.0 (CH3), 20.9 (CH3), 20.5 (CH3), 20.1 (CH3), 14.8 (CH3); MS (CI) m/z (rel intensity) 342 (MH+, 100); HRMS (EI) calcd for C21H27NOS (M+) 341.1813, found 341.1816 (0.8

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ppm); [R]D23 -29.2 (CHCl3, c ) 1). Anal. Calcd for C21H27NOS: C, 73.86; H, 7.97; N, 4.10. Found: C, 73.66; H, 8.11; N, 4.14. Rates of Racemization of 9. The barriers to rotation of the amide axis in compounds 9a-e were established by racemization studies at constant temperature. These studies were carried out by monitoring the optical rotations of solutions of the amides (in chloroform or dioxane, using a mercury source at 578 nm) in a jacketed cell. The cell was kept at constant temperature by pumping water from a thermostatically controlled heating bath through the cell jacket. Observation of the optical rotation (R) over regular time intervals gave a smooth first-order decay curve from which the rate constant for racemization (k) was calculated using the curve-fitting application “Ultrafit” for the Macintosh. Asymmetric Allylic Substitution Reactions.33,34 Potassium acetate (1 mg), N,O-bistrimethylsilyl acetamide (BSA, 609 mg, 3 equiv), dimethyl malonate (396 mg, 3 equiv), and acetate 10 (252 mg, 1 equiv) were added to a solution of allylpalladium dichloride dimer (1.8 mg, 1 mol % Pd) and phosphine 8d (2.5 mg, 0.5 mol %) in dichloromethane (2 mL) under nitrogen. The mixture was stirred at room temperature for 36 h, poured into water, extracted into dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure to give the crude product oil. The crude product was purified by column chromatography (eluting with petrol/EtOAc 9:1) to give the substitution product (-)-12 as a crystalline (33) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. (34) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A. Tetrahedron 1992, 48, 2143.

Clayden et al. solid, with data matching that described in the literature35 and enantiomeric excess of 90% (by HPLC on chiral stationary phase: Regis Whelk-O1 column 4.6 × 250 mm, eluting with 20% IPA in hexane, flow rate 1 mL/min, retention times 10.1 and 11.06 min): mp 95-96 °C; IR (CHCl3)/cm-1 3028, 2952, 1757, 1738;1H NMR (CDCl3, 300 MHz) δ 7.14-7.31 (10H, m), 6.45 (1H, d, 15.5 Hz), 6.29 (1H, dd, 8.5, 15.5 Hz), 4.23 (1H, dd, J ) 8.5, 11.0 Hz), 3.92 (1H, d, J ) 11.0 Hz), 3.67 (3H, s), 3.48 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 168.1, 167.7, 140.1, 136.8, 131.8, 129.1, 128.7, 128.4, 127.8, 127.5, 127.1, 126.4, 57.6, 52.5, 52.4, 49.1; [R]23D -16.9 (CHCl3, c ) 1).

Acknowledgment. We are grateful for grants from the EPSRC and from the Leverhulme Trust. Supporting Information Available: 1H and 13C NMR spectra of compounds 8a-e and 9a-e. X-ray crystal data for (-)-5 and 8d. 1H NMR spectrum of (+)-9b in the presence of (+)-TFAE. This material is available free of charge via the Internet at http://pubs.acs.org. JO0007074 (35) Breeden, S.; Wills, M. J. Org. Chem. 1999, 64, 9735. (36) Higher selectivity may be obtained because the 10:1 ratio of conformers may improve at -78 °C or in THF (though NMR experiments at -30 °C showed conformational ratios similar to those at +25 °C) or because of epimerization of the thermodynamically less stable isomer during the reaction workup. The yield of diastereoisomerically pure 8b suggests that at least in this case this second mechanism is operating.